Nifedipine induces peroxisome proliferator-activated receptor-γ activation in macrophages and suppresses the progression of atherosclerosis in apolipoprotein E-deficient mice

Abstract

Objective: Nifedipine, an L-type calcium channel blocker, protects against the progression of atherosclerosis. We investigated the molecular basis of the antiatherosclerotic effect of nifedipine in macrophages and apolipoprotein E-deficient mice. Methods and results: In macrophages, nifedipine increased peroxisome proliferator-activated receptor-γ (PPARγ) activity without increasing PPARγ-binding activity. Amlodipine, another L-type calcium channel blocker, and 1,2-bis-(o-aminophenoxy)-ethane-N,N,-N′, N′-tetraacetic acid tetraacetoxy-methyl ester (BAPTA-AM), a calcium chelator, decreased PPARγ activity, suggesting that nifedipine does not activate PPARγ via calcium channel blocker activity. Inactivation of extracellular signal-regulated kinase 1/2 suppressed PPARγ2-Ser112 phosphorylation and induced PPARγ activation. Nifedipine suppressed extracellular signal-regulated kinase 1/2 activation and PPARγ2-Ser112 phosphorylation, and mutating PPARγ2-Ser112 to Ala abrogated nifedipine-mediated PPARγ activation. These results suggested that nifedipine inhibited extracellular signal-regulated kinase 1/2 activity and PPARγ2-Ser112 phosphorylation, leading to PPARγ activation. Nifedipine inhibited lipopolysaccharide-induced monocyte chemoattractant protein-1 expression and induced ATP-binding cassette transporter A1 mRNA expression, and these effects were abrogated by small interfering RNA for PPARγ. Furthermore, in apolipoprotein E-deficient mice, nifedipine treatment decreased atherosclerotic lesion size, phosphorylation of PPARγ2-Ser112 and extracellular signal-regulated kinase 1/2, and monocyte chemoattractant protein-1 mRNA expression and increased ATP-binding cassette transporter A1 expression in the aorta. Conclusion: Nifedipine unlike amlodipine inhibits PPARγ-Ser phosphorylation and activates PPARγ to suppress monocyte chemoattractant protein-1 expression and induce ATP-binding cassette transporter A1 expression in macrophages. These effects may induce antiatherogenic effects in hypertensive patients. © 2010 American Heart Association, Inc.